tbuckley/cabot-search huggingface dataset:
Abstract 101: JAK-independent STAT5 signaling as a node of therapeutic vulnerability in glioblastoma
Authors: Mylan Blomquist, Serdar Tuncali, Christopher Sereduk, Jean Kloss, Joseph Loftus, Nhan Tran
Journal: Cancer Research (2022)

Abstract Glioblastoma (GBM), the most common primary brain tumor in adults, comprises all WHO Grade IV gliomas of astrocytic origin. Despite extensive characterization of the molecular and genetic features of GBM, there remains a paucity of viable treatment options, and this disease confers a dismal 5% 5-year survival rate. Genomic amplification of epidermal growth factor receptor (EGFR) occurs in 40-60% of primary GBM. Half of all EGFR-amplified cases of GBM also harbor EGFRvIII, a constitutively active, truncated variant of EGFR. EGFR and EGFRvIII transduce oncogenic signals via cytoplasmic mediators, including the JAK/STAT signal transduction pathway. The oncogenic role of STAT3 has been well-studied in CNS malignancies; STAT3 has been found to induce the expression of target genes involved in the proliferative and invasive phenotypes of GBM. However, little is known about the mechanism and role of STAT5 activation in GBM progression. Microenvironmental cues and EGFRvIII signaling, lost in adherent cell culture, are required for STAT5 activation, making STAT5 difficult to study by conventional cell culture methods. Our recent data from patient-derived xenograft (PDX) cultures demonstrates that activation of STAT5 is important in GBM cell invasion and survival. Further, STAT5 activation is present predominantly at the invasive periphery of the tumor. In this study, we seek to characterize the mechanism and role of STAT5 activation downstream of EGFRvIII in GBM. RNA sequencing of PDX tumors expressing stable shRNA knockdown of STAT3 or STAT5 indicate both redundant and distinct transcriptional changes induced by STAT3 and STAT5 in GBM. We also find that while STAT3 activation is dependent upon JAK1/2, STAT5 activation is JAK-independent downstream of EGFRvIII in GBM. Depletion of JAK1/2 expression by siRNA oligonucleotides and pharmacologic inhibition of JAK1/2 suppressed STAT3 activation but not STAT5. In fact, targeting JAK2 with kinase inhibitor WP1066 suppressed STAT3 activation, but increased activation of STAT5 in GBM cells expressing EGFR/EGFRvIII. Inhibition of Src family kinases (SFK), a family of upstream signaling effectors of the JAK/STAT pathway, attenuates both STAT3 and STAT5 activation. These results suggest that activation of STAT5 may provide a therapeutic escape mechanism to JAK-STAT3 inhibition in GBM, necessitating dual STAT3 and STAT5 inhibition to successfully inhibit the distinct oncogenic signals transmitted by STAT3 and STAT5 to promote GBM cell survival and resistance. Citation Format: Mylan Blomquist, Serdar Tuncali, Christopher Sereduk, Jean Kloss, Joseph Loftus, Nhan Tran. JAK-independent STAT5 signaling as a node of therapeutic vulnerability in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 101.
Abstract 5363: The preclinical selectivity and activity of APS03118, a highly selective and potent next-generation RET inhibitor
Authors: Alexander Drilon, Jun Zhong, Ying Lu, Yongbo Liu, Hao Wang, Minchun Chen, Xiaohu Chen, John Zhu, Shun Lu, Vivek Subbiah
Journal: Cancer Research (2022)

Abstract Backgroud: Oncogenic RET is an actionable target across a variety of cancers. Selective RET inhibitors selpercatinib and pralsetinib were recently approved by the FDA and EMA for patients with RET-dependent NSCLC and thyroid cancers. The solvent front mutations (SFMs) RET G810C/S/R have been identified as mechanisms of acquired resistance to both drugs. The gatekeeper RET V804 mutation cannot be inhibited by selected next-generation RET inhibitors in development. APS03118 is a novel next-generation RET inhibitor which is potent against a range of RET fusions and mutations including both SFMs and gatekeeper mutations. Methods: The selectivity, anti-RET activity, and intracranial efficacy of APS03118 were confirmed in vitro and in vivo in a variety of RET-dependent tumor models. Results: APS03118 was highly selective against a panel of 468 kinases and demonstrated 130-fold selectivity over VEGFR-2. In enzymatic assays, APS03118 showed low nanomolar potency against wild type RET and 25 RET mutations/fusions, including the inhibition of RET G810R/C/S (IC50 0.04-5 nM) and RET V804M/L/E (IC50 0.04-1 nM). APS03118 inhibited RET phosphorylation (IC50 &amp;lt;15 nM) in Ba/F3 engineered RET cells (WT, G810R, V804M, M918T). In cell proliferation assays, APS03118 potently inhibited KIF5B-RET Ba/F3 (WT, V804M, V804L, M918T), CCDC6-RET Ba/F3 (WT, V804M, S904F), LC2/ad (CCDC6-RET), TT (RET C634W) (IC50 &amp;lt; 10nM); Ba/F3 RET G810R and G810S IC50 (8-65 nM). APS03118 demonstrated marked anti-tumor efficacy in vivo in RET-driven cell-derived (Ba/F3 KIF5B-RET, V804M, TT (C634W)) and patient-derived (KIF5B-RET, CCDC6-RET, CCDC6-RET V804M) xenograft tumor models. At 10 mg/kg BID, tumor regression was observed in these xenograft models (TGI 87-108%). Tumors completely subsided in CCDC6-RET orthotopic brain model with a 100% survival rate. In the Ba/F3 KIF5B-RET G810R xenograft model, APS03118 30 mg/kg BID showed 90% TGI and was well tolerated, and RET G810 mutations often drive clinical progression on current RET inhibitors. Conclusions: APS03118 is a novel highly selective next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFMs-mediated resistance. A first-in-human phase 1 trial for patients with RET-driven solid tumors with activating RET alterations is planned for 2022. Citation Format: Alexander Drilon, Jun Zhong, Ying Lu, Yongbo Liu, Hao Wang, Minchun Chen, Xiaohu Chen, John Zhu, Shun Lu, Vivek Subbiah. The preclinical selectivity and activity of APS03118, a highly selective and potent next-generation RET inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5363.
Abstract 5970: Tumor vessel normalization by a novel anti-TIE2 antibody PMC-403 enhances the effectiveness of radiation therapy on cancer therapy
Authors: Eun-Ah Lee, Beom Yong Park, Nuri Kang, Cheon Ho Park, Weon Sup Lee
Journal: Cancer Research (2022)

Abstract Purpose: The delivery of drugs and immune cells into the tumor microenvironment is limited due to abnormal tumor vessel which is characterized as low oxygen concentration, low perfusion rate and leakage. It leads to diminish the efficacy radiation therapy. Traditional anti-angiogenesis strategies attempt to reduce the tumor vascular supply, but their success is restricted by insufficient efficacy or development of resistance. To solve the problem, we try to using PMC-403, which can normalize the abnormal condition of tumor vessel. Experimental procedures: Target selectivity: It was measured by Surface Plasmon Resonance (SPR) assay. Human TIE2 Cho-K1 cells or mouse TIE2 Cho-K1 cells were tested for species cross-reactive assay based on flow cytometry (FACS).In vitro studies: Human umbilical vein endothelial cells (HUVEC) were used for TIE2 signal pathway analysis with western blot assay and efficacy analysis with VEGF-induced vessel permeability assay.In vivo study: Glioblastoma model mice were employed for the assessment of tumor vessel normalizing activity of 1 mg/mouse PMC-403. CT26 colon cancer model mice were used to evaluate the anti-tumor efficacy of PMC403 (10 mg/kg) in combination with radiation therapy. Hypoxyprobe was used to measure the improvement of hypoxic conditions in tumor tissue. Summary of data: PMC-403 has a nanomolar range of affinity for both human or mouse TIE2 expressing cells. This contributed to dose-dependent ANG1-like TIE2 and FOXO1 phosphorylation and inhibited VEGF-induced vascular leakage, thereby contributing to ANG1-like vascular normalization. Moreover, similar to ANG-1, p-VEGFR2 and p-VE-Cadherin levels were significantly reduced by PMC-403, suggesting that PMC-403 can normalize blood vessels. In addition, PMC-403 stabilized abnormal tumor blood vessels in the glioblastoma mouse model and significantly reduced tumor growth and tumor hypoxia in the combination treatment (PMC-403 + radiation therapy) compared to radiation therapy alone, although the antitumor effect of PMC-403 alone was not effective in the same condition model. Conclusions: PMC-403, an anti-TIE2 monoclonal antibody, is a novel tumor vessel stabilizer. PMC-403 improved tumor microenvironment hypoxic condition that synergized with radiotherapy when it combined together for the anticancer therapy. These data strongly support the notion that PMC-403 can effectively treat tumors even with low doses of radiation by stabilizing tumor blood vessels. Citation Format: Eun-Ah Lee, Beom Yong Park, Nuri Kang, Cheon Ho Park, Weon Sup Lee. Tumor vessel normalization by a novel anti-TIE2 antibody PMC-403 enhances the effectiveness of radiation therapy on cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5970.
Abstract 105: Inhibitory effect of Wnt/β-Catenin inhibitor CWP232228 on the growth of ovarian cancer cells
Authors: So-Jin Shin, Seungmee Lee, Hyewon Chung, Chi-Heum Cho, Eunyoung Ha, Jin Young Kim, Ji Hae Seo
Journal: Cancer Research (2022)

Abstract Ovarian cancer is a leading cause of death of women in worldwide. Frequent recurrence and becoming resistant to chemotherapy are one of the causes that makes ovarian cancer deadly. Since recent studies have demonstrated that aberrant Wnt signaling plays an important role in cancer stem cells (CSCs) which are responsible of recurrence, metastasis and treatment failure, we tested whether regulation of Wnt signaling can be effective in ovarian cancer treatment. By treating CWP232228 which is a potent inhibitor of Wnt signaling to ovarian cancer cell lines and to a mouse model, we found CWP232228 effectively inhibits the growth of ovarian cancer cells which expresses high level of b-catenin and induce apoptosis of ovarian cancer cells. Furthermore CWP232228 reduces ovarian cancer cell migration, invasion and colony formation ability. Moreover CWP232228 reduces key features of CSCs. Taken together, our study suggests CWP232228 as a potential substance which might be effective in treating epithelial ovarian cancer with avoiding treatment failure. Citation Format: So-Jin Shin, Seungmee Lee, Hyewon Chung, Chi-Heum Cho, Eunyoung Ha, Jin Young Kim, Ji Hae Seo. Inhibitory effect of Wnt/β-Catenin inhibitor CWP232228 on the growth of ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 105.
Abstract 3723: Role of KAT5 in non-small cell lung cancer
Authors: Daisuke Jefferson Shibahara, Naoki Akanuma, Eunyoung Heo, Mariko Ando, Ikei S. Kobayashi, Masanori Fujii, Prin Paul, Gilbert Pan, Danniel G. Tenen, Hideo Watanabe, Susumu S. Kobayashi
Journal: Cancer Research (2022)

Abstract Histone modifications play crucial roles in transcriptional activation, and aberrant epigenetic changes are associated with oncogenesis. Lysine (K) acetyltransferases 5 (KAT5) is reportedly implicated in cancer development and maintenance, although the role of KAT5 in lung cancer largely remain unclear. Here we demonstrate that KAT5 expression was lower in lung adenocarcinoma than normal lung cells. Overexpression of KAT5 had no effect on tumor proliferation and migration, whereas knockdown of KAT5 paradoxically decreased those activities. To assess KAT5 function in lung tumorigenesis in adults, we generated a lung cancer mouse model in which Kat5 is conditionally deleted in lung. We achieved this by crossing lung-specific EGFR-L858R-T790M transgenic mice with conditional Kat5 knockout mice, and found that complete deletion of Kat5 resulted in suppression of tumor formation. To investigate downstream genes of KAT5, we performed RNA sequencing and chromatin immunoprecipitation sequencing analysis using H1975 KAT5 inducible knockdown cells and control cells. We identified a transglutaminase enzyme, TGM5, as one of downstream of KAT5. We furthermore identified artemisinin, an anti-malarial drug, as a potent KAT5 inhibitor by using the connectivity map database, and treatment with artemisinin suppressed tumor growth and induced apoptosis in vitro an in vivo. Taken together, suppression of KAT5 activity shows a tumor-specific efficacy against lung cancer in which KAT5 expression is lower, with no definite influence on normal tissues. Thereby, targeting KAT5 is a potent candidate for the treatment of lung cancer. Citation Format: Daisuke Jefferson Shibahara, Naoki Akanuma, Eunyoung Heo, Mariko Ando, Ikei S. Kobayashi, Masanori Fujii, Prin Paul, Gilbert Pan, Danniel G. Tenen, Hideo Watanabe, Susumu S. Kobayashi. Role of KAT5 in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3723.
DigestPath: A benchmark dataset with challenge review for the pathological detection and segmentation of digestive-system
Authors: Qian Da, Xiaodi Huang, Zhongyu Li, Yanfei Zuo, Chenbin Zhang, Jingxin Liu, Wen Chen, Jiahui Li, Dou Xu, Zhiqiang Hu, Hongmei Yi, Yan Guo, Zhe Wang, Ling Chen, Li Zhang, Xianying He, Xiaofan Zhang, Ke Mei, Chuang Zhu, Weizeng Lu, Linlin Shen, Jun Shi, Jun Li, Sreehari S, Ganapathy Krishnamurthi, Jiangcheng Yang, Tiancheng Lin, Qingyu Song, Xuechen Liu, Simon Graham, Raja Muhammad Saad Bashir, Canqian Yang, Shaofei Qin, Xinmei Tian, Baocai Yin, Jie Zhao, Dimitris N. Metaxas, Hongsheng Li, Chaofu Wang, Shaoting Zhang
Journal: Medical Image Analysis (2022)
Screening for Primary Open-Angle Glaucoma
Authors: Carol M. Mangione, Michael J. Barry, Wanda K. Nicholson, Michael Cabana, David Chelmow, Tumaini Rucker Coker, Esa M. Davis, Katrina E. Donahue, John W. Epling, Carlos Roberto Jaén, Alex H. Krist, Martha Kubik, Li Li, Gbenga Ogedegbe, Lori Pbert, John M. Ruiz, Melissa A. Simon, James Stevermer, John B. Wong
Journal: JAMA (2022)

<h3>Importance</h3> Glaucoma affects an estimated 2.7 million people in the US. It is the second-leading cause of irreversible blindness in the US and the leading cause of blindness in Black and Hispanic/Latino persons. <h3>Objective</h3> To update its 2013 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of screening for glaucoma in adults. <h3>Population</h3> Adults 40 years or older who present in primary care and do not have signs or symptoms of open-angle glaucoma. <h3>Evidence Assessment</h3> The USPSTF concludes that the evidence is insufficient to assess the balance of benefits and harms of screening for glaucoma in adults. The benefits and harms of screening for glaucoma in adults are uncertain. More research is needed. <h3>Recommendation</h3> The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for primary open-angle glaucoma in adults. (I statement)
Abstract 5960: Blood-based extracellular vesicle biomarker test for detection of early-stage pancreatic cancer
Authors: Juan P. Hinestrosa, Jean M. Lewis, Heath I. Balcer, Razelle Kurzrock, Scott Lippman, Rajaram Krishnan
Journal: Cancer Research (2022)

Abstract Pancreatic cancer is an almost uniformly lethal malignancy, in large part because is it rarely detected in its early, curable stages. We recently conducted a study to evaluate the use of proteins associated with extracellular vesicles (EVs) isolated using an alternating current electrokinetic (ACE) system for the early detection of pancreatic ductal adenocarcinoma. Because earlier detection of pancreatic cancer greatly improves outcomes, we sought to devise a blood-based test with high specificity for detecting early-stage PDAC based on identification of EV-bound biomarkers. EVs were purified from control or stage I-II pancreatic ductal adenocarcinoma (PDAC) patient plasma using an ACE microelectrode array. Following collection of EVs onto the electrodes, contaminating plasma elements were washed away, and the electric field was turned off to release EVs into buffer. The isolated EV/exosome samples were then tested using bead-based multiplex immunoassay kits to determine relative concentrations of biomarkers of interest. Sample cohorts were divided into a training set (controls, N=146; PDAC cases, N=33) to develop a logistic regression-based classification model, and a validation set (controls, N=139; PDAC cases, N=35) to generate a probability-based score for predicting the presence of PDAC. For the training set, the algorithm identified six protein biomarkers associated with the presence of stages I-II cancer in PDAC patient plasma, with a receiver-operating characteristic (AUC) of 0.997 (95% CI: 0.978-1.000) compared to control plasma samples. For the validation set, the algorithm had a sensitivity of 82.9% (95% CI: 67.3% - 91.9%) at a specificity of 99.3% (95% CI: 96.0% - 99.9%), generating an AUC = 0.978 (95% CI=0.954-0.995). The exosomal PDAC assay shows feasibility for developing minimally invasive liquid biopsies that allow low-risk, routine screening of high-risk patients. Those patients identified by the test would be able to undergo additional testing to determine if there is PDAC present. The additional screening and testing of these patients may increase the likelihood of curative treatment. Further work in large datasets is warranted. Citation Format: Juan P. Hinestrosa, Jean M. Lewis, Heath I. Balcer, Razelle Kurzrock, Scott Lippman, Rajaram Krishnan. Blood-based extracellular vesicle biomarker test for detection of early-stage pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5960.
Abstract 5428: Evaluating cancer therapies combining radiotherapy with immunotherapy or inhibitors of the DNA damage response
Authors: Feifei Fan
Journal: Cancer Research (2022)

Abstract Ionizing radiation has largely been recognized as a local targeted therapy by a variety of mechanisms, including inducing direct DNA damage of cancerous tissue or contributing to systemic antitumor immunity. The capacity of cancer cells to recognize DNA damages and initiate repair plays a major role in radio-resistance. Furthermore, the irradiated tumor cell death can enhance antitumor immunity by inducing antigen expression on tumor cells and activating lymphocytes. Recent evidence indicates that cancer cells can be made more sensitive to the effects of radiation (radio-sensitization) through inhibition of DNA repair pathways, and a growing body of evidence indicates that cancer immunotherapy may also have radio-sensitizing effects. The combination of radiation therapy and DDR inhibitors/immunotherapy presents a promising strategy for cancer therapy.In order to provide guidance on clinical therapeutic strategy selection, we established a beam-focused radiation platform (RadSource 2000 X-ray irradiator) to evaluate the anti-tumor efficacy of fractionated radiotherapy combination in a panel of cell lines and mouse models. We have tested the combination effect of DDR inhibitor in combination with radiotherapy in vitro and in vivo, both showing radio-sensitization effects and improvement in anti-tumor activity. We have also chosen several syngeneic models to test the combination strategy of radiotherapy and immune checkpoint inhibitors (PD-1 and PD-L1), and performed TIL analysis to explore the possible mechanisms of combination effect. In summary, our beam-focused radiation platform provides insights into the design of new therapeutic strategies and has become an effective tool in pre-clinical research of anti-cancer therapy. Citation Format: Feifei Fan. Evaluating cancer therapies combining radiotherapy with immunotherapy or inhibitors of the DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5428.
Abstract 3055: Field cancerization and microbiome in lung cancer
Authors: Rayan I. Alhammad, Ngoc B. Vuong, Weidong Zhou, Claudius Mueller, Donald J Johann, Amith R. Katta, Monique V. Hoek, Fahad M. Alsaab, Alessandra Luchini, Lance Liotta
Journal: Cancer Research (2022)

Abstract Lung Cancer carcinogenesis is the outcome of a field of premalignant changes that occur in the bronchial tree leading to the overt emergence of the malignant lung cancer. We sought to study the proteome of the microbiome associated with the premalignant bronchial mucosa epithelia. The overall goal is the identify functional relationships between the bronchial mucosa microbiome and the risk of developing lung cancer. We evaluated the proteome of the microbiome using mass spectrometry and specialized microbiome authentication software. This method was applied to a case-control study of plasma samples donors of physician health study who donated plasma at different times prior to the onset of Non-Small Cell Lung Cancer. We also examined bronchial mucosa tissue samples near to, and distant from, the tumor harvested from surgical lobectomy specimens. Highly significant protein biomarker differences were found in the plasma and in the tissue samples that were blindly associated with cancer. These included specific proteins from the mucosal microbiome that may have functional role in the carcinogenic process. These key diagnostic risk markers were shared between the premalignant bronchial mucosa tissue and the plasma, supporting the concept that risk markers of bronchial mucosa lung cancer carcinogenesis can be detected in the peripheral circulation. Citation Format: Rayan I. Alhammad, Ngoc B. Vuong, Weidong Zhou, Claudius Mueller, Donald J Johann Jr, Amith R. Katta, Monique V. Hoek, Fahad M. Alsaab, Alessandra Luchini, Lance Liotta. Field cancerization and microbiome in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3055.